The present invention relates to inhibiting an immune response to an alloantigen and further relates to inhibiting and/or preventing reactivation of previously activated T cells. More particularly, the present invention relates to the field of preventing, reducing or treating an immune response caused by immune effector cells to foreign tissue and/or cells and/or organs. The invention further relates to preventing, reducing or treating transplant rejection and/or graft versus host reaction.
Tolerance is the acquired lack of specific responsiveness to an antigen to which an immune response would normally occur. Typically, to induce tolerance, there must be an exposure to a tolerizing antigen, which results in the death or functional inactivation of certain lymphocytes. Complete tolerance is characterized by the lack of a detectable immune response to the second antigenic challenge. Partial tolerance is typified by the quantitative reduction of an immune response.
Unfortunately, the immune system does not distinguish beneficial intruders, such as transplanted tissue, from those that are harmful, and thus the immune system rejects transplanted tissue or organs. Rejection of transplanted organs is significantly mediated by alloreactive T cells present in the host which recognize donor alloantigens or xenoantigens.
At present, in order to prevent or reduce an immune response against a transplant, patients are treated with powerful immunosuppressive drugs. The infusion of individuals with drugs that prevent or suppress a T-cell immune response does inhibit transplant rejection, but can also result in general immune suppression, toxicity and even death due to opportunistic infections. Because of the toxicity and incomplete response rate to conventional treatment of donor tissue rejection, alternative approaches are needed to treat patients who cannot withstand or do not respond to current modes of drug therapy.
Accordingly, there is a need for the prevention and/or reduction of an unwanted immune response by a host to a transplant by immune effector cells as a method to avert host rejection of donor tissue. Also advantageous would be a method to eliminate or reduce an unwanted immune response by a donor tissue against a recipient tissue, known as graft-versus-host disease.
It has been discovered that mesenchymal stem cells (MSCs) can induce allo-activated T-cells to become suppressive for allogeneic responses, and that human suppressor cells can be used in transplantation to ameliorate a response by the immune system such that an immune response to an antigen(s) will be reduced or eliminated.
In accordance with one aspect of the invention, there is provided a method for reducing or suppressing an immune response caused by T cells responding to an alloantigen, in particular allogeneic tissue, organ or cells, wherein the immune response is reduced or suppressed by the use of suppressor T cells. The suppressor T cells may be autologous to the T cells (obtained from the same host), or may be allogeneic to the T-cells.
In accordance with another aspect of the present invention there is provided a process for preventing restimulation of activated T cells (activated against an alloantigen, in particular an allogeneic organ, tissue or cells) by contacting activated T cells with suppressor T cells in an amount effective to prevent and/or reduce a subsequent T cell response to a foreign antigen. The mesenchymal stem cells that are used may be autologous to the T cells, or may be allogeneic to the T-cells. Preferably, the mesenchymal stem cells are autologous to the T-cells.
In accordance with another aspect of the present invention, suppressor T cells are used to suppress or ameliorate an immune response to a transplant (tissue, organ, cells, etc.) by administering to the transplant recipient suppressor T cells in an amount effective to suppress or ameliorate an immune response against the transplant. The suppressor T cells may be autologous to the transplant recipient, or the suppressor T-cells may be allogeneic to the transplant recipient. Preferably, the suppressor T-cells are autologous to the transplant recipient.
Accordingly, one method of the present invention provides contacting the recipient of donor tissue with autologous suppressor T cells. In one embodiment of this aspect, the method involves administering suppressor T cells to the recipient of donor tissue. The suppressor T cells can be administered to the recipient before or at the same time as the transplant or subsequent to the transplant.
The suppressor T cells can also be administered to the recipient as part of the transplant. To this objective, the present invention provides a method for reducing or ameliorating an immune response by providing to the recipient donor tissue or organ that is perfused with or includes suppressor T cells autologous to the T cells. The suppressor T cells ameliorate an immune response by the recipient""s T cells against the foreign tissue when it is transplanted into the recipient.
In another embodiment, the method of the present invention provides treating a patient who has received a transplant, in order to reduce the severity of or eliminate a rejection episode against the transplant, by administering to the recipient of donor tissue suppressor T cells after the donor tissue has been transplanted into the recipient. The suppressor T cells preferably are autologous to the recipient. The presentation of suppressor T cells to a recipient undergoing an adverse immune response to a transplant induces nonresponsiveness of T cells to further antigenic stimulation thereby reducing or eliminating an adverse response by activated T cells to donor tissue or organ.
In a further aspect of the present invention, there is provided a method of reducing an immune response by donor tissue, organ or cells against a recipient, i.e. graft versus host response, comprising treating the donor tissue, organ or cells with suppressor T cells ex vivo prior to transplantation of the tissue, organ or cells into the recipient. The suppressor T cells reduce the responsiveness of T cells in the transplant that may be subsequently activated against recipient antigen presenting cells such that the transplant may be introduced into the recipient""s (host""s) body without the occurrence of, or with a reduction in, an adverse response of the transplant to the host. Thus, what is known as xe2x80x9cgraft versus hostxe2x80x9d disease may be averted.
In a preferred embodiment, the donor transplant may be first exposed to recipient or third party tissue or cells ex vivo, to activate the T cells in the donor transplant. The donor transplant is then contacted with suppressor T cells. The suppressor T cells will reduce or inhibit an adverse secondary immune response by T cells in the donor transplant against antigenic stimulation by the recipient when the donor transplant is subsequently placed into the recipient.
The suppressor T cells can be obtained from the recipient prior to the transplant. The suppressor T cells can be isolated and stored frozen until needed. The suppressor T cells may also be culture-expanded to desired amounts and stored until needed. The suppressor T cells are administered to the recipient in an amount effective to reduce or eliminate an ongoing adverse immune response caused by the donor transplant against the recipient (host). The presentation of the suppressor T cells to the recipient undergoing an adverse immune response caused by a transplant inhibits the ongoing response and prevents restimulation of the T cells thereby reducing or eliminating an adverse response by activated T cells to recipient tissue.
Thus, in accordance with preferred embodiments of the present invention, human suppressor T cells are employed to treat transplant rejection and or graft versus host disease as a result of a transplant and or to prevent or reduce transplant rejection and or graft versus host disease. Human suppressor T cells may also be employed to facilitate the use of xenogeneic grafts or transplants.